The development of an animal model system for infection and disease by HIV-1 is essential for AIDS vaccine studies and intervention. Although chimpanzees can be infected with HIV-1, this is not a very useful model since this species is very expensive to maintain and restricted in numbers for experimental studies. Recently, pig-tailed macaques have been shown to be susceptible to HIV-1 infection (Agy, et al., 1992). Infected animals were followed for about one year. In general there was early, transient virus replication and persistence of viral sequences in the PBMCs; however, no clinical changes were seen. Based upon the initial report, we infected 2 pig-tailed macaques (designated as PT 86 and PT 99) with HIV-1/LAI and have followed the kinetics of infection for 3 years in these animals. Our results confirm previous studies showing infection at one year post-inoculation. We have extended these results to show that the animals remain infected at 3 years post-inoculation: 1)HIV-1 sequences persited in the lymph nodes of both animals; 2) strong antibody response was maintained in both animals, with neutralizing antibodies detected at various times; and 3) a gradual, decreasing CD4+/CD8+ ratio was seen in PT 86 (manuscript in prep.). Since the clinical symptoms of AIDS in humans generally develop in 5-10 years, it is most likely too early to see clinical symptoms in the infected animals. These results suport that pig-tailed macaques can be a useful model for HIV-1 infection studies. Current efforts are directed towards developing monkey-tropic HIV-1 that can efficiently replicate in monkey cells and perhaps produce disease. We are pursuing two approaches to create such a mutant HIV-1: 1) construction of recombinant HIV and SIV viral DNA to produce infectious chimeric virus (SHIV); and 2) monkey cell-adaptation of HIV-1 by passaging thru monkey PBMCs. Well-characterized monkey-tropic HIV-1 stocks will be useful in infectivity studies as well as in protection studies to test efficacy of anti-viral agents against challenge virus.